The present invention is directed to novel taxanes which have utility as antitumor agents and to a process for their preparation.
The taxane family of terpenes, of which baccatin III and taxol are members, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of tumor-inhibiting activity. Taxol has a 2xe2x80x2R, 3xe2x80x2S configuration and the following structural formula: 
wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
Colin et al. reported in U.S. Pat. No. 4,814,470 that taxol derivatives having the structural formula (II) below, have an activity significantly greater than that of taxol (I). 
Rxe2x80x2 represents hydrogen or acetyl and one of Rxe2x80x3 and Rxe2x80x2xe2x80x3 represents hydroxy and the other represents tert-butoxycarbonylamino and their stereoisomeric forms, and mixtures thereof. The compound of this formula in which Rxe2x80x3 is hydroxy, Rxe2x80x2xe2x80x3 is tert-butoxycarbonylamino having the 2xe2x80x2R, 3xe2x80x2S configuration is commonly referred to as taxotere.
Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents.
Among the objects of the present invention, therefore, is the provision of novel taxanes which are valuable anti-tumor agents and a process for their preparation.
Briefly, therefore, the present invention is directed to a process for the preparation of 1-deoxy baccatin III, 1-deoxy taxol and 1-deoxy taxol analogs. The process comprises at least one of the following steps:
(a) reacting a compound having the formula: 
with a peracid such as metachloroperbenzoic acid to form a compound having the formula: 
wherein P10 is a silyl hydroxy protecting group such as triethylsilyl or an acyl group such as benzoyl. In this reaction, the protected hydroxy group xe2x80x94OP10 migrates to the adjacent carbon and becomes xe2x80x94OP9 with P9 being the same as P10;
(b) subjecting a compound having the formula: 
to an epoxy alcohol fragmentation consisting of (ia) epoxidation of an olefinic residue with a hydroperoxide, preferably t-BuOOH, in the presence of a transition metal catalyst, preferably titanium tetraisopropoxide, or (ib) treatment of the olefinic residue with a peracid such as peracetic acid followed by (ii) addition of a sulfide, preferably dimethyl sulfide, followed by heating in the presence of a transition metal catalyst, preferably titanium tetraisopropoxide, to form a compound having the formula: 
wherein P9 is a hydroxyl protecting group such as a silyl group, ketal, acetal, or ether which does not contain a reactive functionality;
(c) reacting a compound having the formula: 
with a vinyl organometallic reagent to form a compound having the formula: 
(d) reacting a compound having the formula: 
with a paladium catalyst to form a compound having the formula: 
(e) reacting a compound having the formula: 
with a base, most preferably BaO in methanol, and protecting the C7 hydroxy substituent, for example, by reacting the product with TESOTf, to form a compound having the formula: 
(f) reacting a compound having the formula: 
with SeO2 to form a compound having the formula: 
wherein E7 is hydrogen or a hydroxy protecting group, and P2, P7, P9, P10 and P13 are hydroxy protecting groups as hereinafter defined.
In general, the process of the present invention may be used to prepare 1-deoxy baccatin III, 1-deoxy taxol and 1-deoxy taxol analogs having the formula: 
wherein
M comprises ammonium or is a metal;
R2 is xe2x80x94OT2, xe2x80x94OCOZ2, or xe2x80x94OCOOZ2;
R4 is xe2x80x94OT4, xe2x80x94OCOZ4, or xe2x80x94OCOOZ4;
R6 is hydrogen, keto, xe2x80x94OT6, xe2x80x94OCOZ6 or xe2x80x94OCOOZ6;
R7 is hydrogen, halogen, xe2x80x94OT7, xe2x80x94OCOZ7 or xe2x80x94OCOOZ7;
R9 is hydrogen, keto, xe2x80x94OT9, xe2x80x94OCOZ9 or xe2x80x94OCOOZ9;
R10 is hydrogen, keto, xe2x80x94OT10, xe2x80x94OCOZ10 or xe2x80x94OCOOZ10;
R6, R7, R9, and R10 independently have the alpha or beta stereochemical configuration;
R13 is hydroxy, protected hydroxy, keto, MOxe2x80x94 or 
T2, T4, T6, T7, T9 and T10 are independently hydrogen or hydroxy protecting group;
X1 is xe2x80x94OX6;
X2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl;
X3 and X4 are independently hydrogen, hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl;
X5 is xe2x80x94COX10, xe2x80x94COOX10, xe2x80x94COSX10, or xe2x80x94CONX8X10;
X6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, or hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
X8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon;
X10 is hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl; and
Z2, Z4, Z6, Z7, Z9 and Z10 are independently hydrocarbon, heterosubstituted hydrocarbon, or heteroaryl.
The present invention is additionally directed to compounds having the formulae 
wherein E7 is hydrogen or a hydroxy protecting group; Bz is benzoyl; P2, P3, P7, P9, P10 and P13 are hydroxy protecting groups; and R13 is as previously defined. These compounds are key intermediates in the synthesis of 1-deoxy baccatin III, 1-deoxy taxol and other analogs. The present invention is also directed to processes for the preparation of these key intermediates.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
The process of the present invention enables the preparation of 1-deoxy taxol, 1-deoxy taxotere and analogs of 1-deoxy taxol and 1-deoxy taxotere from 1-deoxy baccatin III, 1-deoxy-10-deactylbaccatin III, or analogs thereof. In a preferred embodiment, these compounds have the formula: 
wherein
M comprises ammonium or is a metal;
R2 is xe2x80x94OCOZ2;
R4 is xe2x80x94OCOZ4;
R6 is hydrogen;
R7 is hydrogen, xe2x80x94OT7, or xe2x80x94OCOZ7;
R9 is hydrogen, keto, xe2x80x94OT9, xe2x80x94OCOZ9;
R10 is hydrogen, keto, xe2x80x94OT10, or xe2x80x94OCOZ10;
R13 is MOxe2x80x94 or 
T7, T9 and T10 are independently hydrogen or hydroxy protecting group;
X1 is xe2x80x94OX6;
X2 is hydrogen;
X3 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, or heteroaryl;
X4 is hydrogen;
X5 is xe2x80x94COX10 or xe2x80x94COOX10;
X6 is hydrogen or hydroxy protecting group;
X10 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, or heteroaryl; and
Z2 is alkyl, substituted alkyl, phenyl, substituted phenyl, or heteroaryl;
Z4 is phenyl, substituted phenyl, or heteroaryl; and
Z7, Z9 and Z10 are independently alkyl, substituted alkyl, phenyl, substituted phenyl, or heteroaryl.
An exemplary synthesis of 1-deoxy baccatin III is depicted in Reaction Scheme 1. The starting material, diol 1, can be prepared from patchino (commonly known as B-patchouline epoxide) which is commercially available. The patchino is first reacted with an organo-metallic, such as lithium t-butyl followed by oxidation with an organic peroxide, such as t-butylperoxide in the presence of titanium tetraisopropoxide to form a tertiary alcohol. The tertiary alcohol is then reacted with a Lewis acid, such as boron trifluoride at low temperature, in the range from 40xc2x0 C. to xe2x88x92100xc2x0 C.; in the presence of an acid, such as trifluoromethane sulfonic acid. A graphical depiction of this reaction scheme along with an experimental write-up for the preparation of diol 1 can be found in U.S. Pat. No. 4,876,399.
In this reaction scheme, P2 is BOM; P3 is TMS; P7 is Ac in compounds 12-15 and TES in compounds 18-23; P9 is TES in compounds 4, 5, 6 and 7, and TMS in compounds 8, 9, 10, 11 and 12; P10 is TES, and P13 is TBS in compounds 7 through 21 and TES in compounds 22 and 23. It should be understood, however, that P2, P3, P7, P9, P10, and P13 may be other hydroxy protecting groups.
In general, tetracyclic taxanes bearing C13 side chains may be obtained by reacting a xcex2-lactam with alkoxides having the taxane tetracyclic nucleus and a C-13 metallic or ammonium oxide substituent to form compounds having a xcex2-amido ester substituent at C-13. The xcex2-lactams have the following structural formula: 
wherein X1-X5 are as defined above. The alkoxides having the tetracyclic taxane nucleus and a C-13 metallic oxide or ammonium oxide substituent have the following structural formula: 
wherein R2, R4, R6, R7, R9, R10 and R13 are as previously defined and M comprises ammonium or is a metal optionally selected from Group IA, IIA, transition (including lanthanides and actinides), IIB, IIIA, IVA, VA, or VIA metals (CAS version). If M comprises ammonium, it is preferably tetraalkylammonium and the alkyl component of the tetraalkylammonium substituent is preferably C1-C10 alkyl such as methyl or butyl.
1-Deoxytaxol may be prepared by protecting the C7 hydroxy group of 1-deoxy Baccatin III 24 with a suitable hydroxy protecting group, converting the 7-protected Baccatin III to the corresponding alkoxide and reacting the alkoxide with a xcex2-lactam in which X1 is protected hydroxy, X3 is phenyl, X5 is benzoyl and X2 and X4 are hydrogen. Protecting groups such as 2-methoxypropyl (xe2x80x9cMOPxe2x80x9d), 1-ethoxyethyl (xe2x80x9cEExe2x80x9d), benzyloxymethyl are preferred, but a variety of other standard protecting groups such as trialkyl and triaryl silyl groups may be used.
1-Deoxytaxotere may be prepared in the same manner as 1-deoxytaxol except that 1-deoxy-10-deacetylbaccatin III is used instead of 1-deoxybaccatin III and X5 of the xcex2-lactam is t-butoxycarbonyl instead of benzoyl. 1-deoxy-10-deacetyl-baccatin III may be prepared as set forth in Reaction Scheme 2, starting with compound 22.
Analogs of 1-deoxy taxol and 1-deoxytaxotere bearing alternative side chain substituents may be prepared by using other suitably substituted xcex2-lactams. For example, 1-deoxy taxol and 1-deoxytaxotere analogs having alkyl, alkenyl, alkynyl, substituted aryl, heteroaryl or substituted heteroaryl substituents at the C3xe2x80x2 position are prepared using xcex2-lactams in which X3 is alkyl, alkenyl, alkynyl, substituted aryl, heteroaryl or substituted heteroaryl. Alternatively, X5 of the xcex2-lactam may be xe2x80x94COX10, xe2x80x94COOX10, xe2x80x94COSX10 or xe2x80x94CONX8X10 wherein X8 and X10 are as previously defined.
1-deoxy-10-desacetoxy analogs of taxol can be prepared from the corresponding 1-deoxy-10-desacetoxy derivatives of baccatin III and 1-deoxy-10-desoxy derivatives of 10-DAB. These derivatives may be prepared as illustrated in Reaction Scheme 3 by reacting 1-deoxy-baccatin III or 1-deoxy-10-DAB (or their derivatives) with samarium diiodide. Reaction between the tetracyclic taxane having a C10 leaving group and samarium diiodide may be carried out at 0xc2x0 C. in a solvent such as tetrahydrofuran. Advantageously, the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed. 
Analogs of 1-deoxy taxol and 1-deoxytaxotere having alternative C9 substituents may be prepared by selectively reducing the C9 keto substituent of 1-deoxytaxol, 1-deoxy-10-DAB, 1-deoxybaccatin III or one of the other intermediates disclosed herein to yield the corresponding 9-xcex2-hydroxy-1-deoxy derivative. The reducing agent is preferably a borohydride and, most preferably, tetrabutylammoniumboro-hydride (Bu4NBH4) or triacetoxyborohydride.
As illustrated in Reaction Scheme 4, the reaction of 1-deoxybaccatin III 24 with Bu4NBH4 in methylene chloride yields 9-desoxo-9xcex2-hydroxy-1-deoxybaccatin III 25. After the C7 hydroxy group is protected with a suitable protecting group, a suitable side chain may be attached to 7-protected-9xcex2-hydroxy-1-deoxy derivative 26 as elsewhere described herein. Removal of the remaining protecting groups thus yields 9xcex2-hydroxy-desoxo-1-deoxy taxol or other 9-xcex2-hydroxy-1-deoxytetracylic taxane having a C13 side chain. 
Alternatively, the C13 hydroxy group of 7-protected-9xcex2-hydroxy-1-deoxy derivative 26 may be protected with a protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 5, to enable further selective manipulation of the various substituents of the taxane. For example, reaction of 7,13-protected-9xcex2-hydroxy-1-deoxy derivative 27 with KH causes the acetate group to migrate from C10 to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding 10-desacetyl derivative 28. Protection of the C10 hydroxy group of 10-desacetyl derivative 28 with a protecting group yields derivative 29. Selective removal of the C13 hydroxy protecting group from derivative 29 yields derivative 30 to which a suitable side chain may be attached as described above. 
As shown in Reaction Scheme 6, 10-oxo derivative 31 can be provided by oxidation of 10-desacetyl derivative 28. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxanes having a C13 side chain. Alternatively, the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 31 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 32 from which the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-1-deoxytaxol or other 9-desoxo-10-oxo-1-deoxytetracylic taxanes having a C13 side chain. 
Reaction Scheme 7 illustrates a reaction in which 1-deoxy-10-DAB is reduced to yield tetraol 33. The C7 and C10 hydroxyl groups of tetraol 33 can then be selectively protected with a protecting group to produce diol 34 to which a C13 side chain can be attached as described above or, alternatively, after further modification of the tetracylic substituents. 
Taxanes having C9 and/or C10 acyloxy substituents other than acetoxy can be prepared using 1-deoxy-10-DAB as a starting material as illustrated in Reaction Scheme 8. After protecting the C7 hydroxy of 1-deoxy-10-DAB with a suitable protecting group to yield 7-protected 1-deoxy-10-DAB 35, the C10 hydroxy substituent of 7-protected 1-deoxy-10-DAB 35 may then be readily acylated with any standard acylating agent such as an acid chloride to yield derivative 36 having a new C10 acyloxy substituent. Use of the analogous chloroformate instead of the acid chloride would yield the corresponding carbonate. Deprotection of the C7 hydroxy group, followed by selective reduction of the C9 keto substituent of derivative 36 with tetrabutylammonium borohydride, and then protection of the C7 hydroxy group yields 9xcex2-hydroxy derivative 37 to which a C13 side chain may be attached. Alternatively, the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 5, above. 
Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials. The C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-Al, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine. Alternatively, the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride. See, e.g., U.S. Pat. No. 5,399,726 which is incorporated herein by reference with respect to the preparation of taxanes having different C2 and C4 acyloxy substituents.
In Reaction Scheme 9, 7,10,13-protected 10-DAB 38 is converted to the diol 39 with lithium aluminum hydride. Deprotonation of diol 39 with LDA followed by reaction with an acid chloride selectively gives the C2 ester 40. Deprotonation of the C2 ester 40 with LDA followed by reaction with acid chloride gives the C2, C4 ester 41. If a chloroformate is used instead of the acid chloride, the product is a C2 or C4 carbonate (xe2x80x94OCOOZ2 or xe2x80x94OCOOZ4). 
C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 10, 11 and 12.
As shown in Reaction Scheme 11, 1-deoxy-baccatin III may be converted into 7-fluoro 1-deoxy-baccatin III by treatment with FAR at room temperature in THF solution. Other 1-deoxy-baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-1-deoxy-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride.
Taxanes having C7 acyloxy substituents can be prepared as set forth in Reaction Scheme 12. 7,13-protected 10-oxo-derivative 42 is converted to its corresponding C13 alkoxide by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a xcex2-lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
1-deoxy taxanes having alternative C6 substituents can be prepared using the reactions described in Liang et al., Tetrahedron Letters, Vol. 36, No. 17, pp. 2901-2904 (1995), starting, however, with 1-deoxy-10,13-protected-10-DAB instead of taxol. According to this reaction scheme, 1-deoxy-10,13-protected-10-DAB is converted to the 7-0-triflate using CF3SO2Cl. Treatment of the 7-0-triflate with 1,8-diazabicyclo(5,4,0)-undec-7-ene (DBU) produces the 7-deoxy intermediate which when reacted with OsO4 followed by an acid chloride (or chloroformate) yields the corresponding C6 ester or carbonate.
As used herein, xe2x80x9cArxe2x80x9d means aryl; xe2x80x9cPhxe2x80x9d means phenyl; xe2x80x9cBzxe2x80x9d means benzoyl; xe2x80x9cMexe2x80x9d means methyl; xe2x80x9cEtxe2x80x9d means ethyl; xe2x80x9ciPrxe2x80x9d means isopropyl; xe2x80x9ctBuxe2x80x9d and xe2x80x9ct-Buxe2x80x9d means tert-butyl; xe2x80x9cRxe2x80x9d means lower alkyl unless otherwise defined; xe2x80x9cAcxe2x80x9d means acetyl; xe2x80x9cpyxe2x80x9d means pyridine; xe2x80x9cTESxe2x80x9d means triethylsilyl; xe2x80x9cTMSxe2x80x9d means trimethyl-silyl; xe2x80x9cTBSxe2x80x9d means Me2t-BuSi-; xe2x80x9cTfxe2x80x9d means xe2x80x94SO2CF3; xe2x80x9cBMDAxe2x80x9d means BrMgNiPr2; xe2x80x9cSwernxe2x80x9d means (COCl)2, Et3N; xe2x80x9cLTMPxe2x80x9d means lithium tetramethylpiperidide; xe2x80x9cMOPxe2x80x9d means 2-methoxy-2-propyl; xe2x80x9cBOMxe2x80x9d means benzyloxymethyl; xe2x80x9cLDAxe2x80x9d means lithium diisopropylamide; xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride; xe2x80x9cRed-Alxe2x80x9d means sodium bis(2-methoxyethoxy) aluminum hydride; xe2x80x9cMsxe2x80x9d means CH3SO2xe2x80x94; xe2x80x9cTASFxe2x80x9d means tris(diethylamino)-sulfonium-difluorotrimethylsilicate; xe2x80x9cTsxe2x80x9d means toluene-sulfonyl; xe2x80x9cTBAFxe2x80x9d means tetrabutyl ammonium hydride; xe2x80x9cTPAPxe2x80x9d means tetrapropyl-ammonium perruthenate; xe2x80x9cDBUxe2x80x9d means diazabicycloundecane; xe2x80x9cDMAPxe2x80x9d means p-dimethylamino pyridine; xe2x80x9cLHMDSxe2x80x9d means lithium hexamethyldisilazide; xe2x80x9cDMFxe2x80x9d means dimethylformamide; xe2x80x9cAIBNxe2x80x9d means azo-(bis)-isobutyronitrile; xe2x80x9c10-DABxe2x80x9d means 10-desacetylbaccatin III; xe2x80x9cFARxe2x80x9d means 2-chloro-1,1,2-trifluorotriethylamine; xe2x80x9cmCPBAxe2x80x9d means meta-chloroperbenzoic acid; xe2x80x9cDDQxe2x80x9d means dicyanodichloroquinone; xe2x80x9csulfhydryl protecting groupxe2x80x9d includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; xe2x80x9camine protecting groupxe2x80x9d includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; xe2x80x9cprotected hydroxyxe2x80x9d means xe2x80x94OP wherein P is a hydroxy protecting group; and xe2x80x9chydroxy protecting groupxe2x80x9d includes, but is not limited to, acetals having two to ten carbons, ketals having two to ten carbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-tri-chloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1-6 alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981.
The xe2x80x9chydrocarbonxe2x80x9d moities described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.
The alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
The alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
The alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
The aryl moieties described herein contain from 6 to 20 carbon atoms and include phenyl. They may be hydro-carbon or heterosubstituted with the various substituents defined herein. Phenyl is the more preferred aryl.
The heteroaryl moieties described are heterocyclic compounds or radicals which are analogous to aromatic compounds or radicals and which contain a total of 5 to 20 atoms, usually 5 or 6 ring atoms, and at least one atom other than carbon, such as furyl, thienyl, pyridyl and the like. The heteroaryl moieties may be substituted with hydrocarbon, heterosubstituted hydrocarbon or hetero-atom containing substituents with the hetero-atoms being selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, and halogens. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; amino; and amido.
The heterosubstituted hydrocarbon moieties described herein are hydrocarbon moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; amino; and amido.
The acyl moieties described herein contain hydrocarbon, substituted hydrocarbon or heteroaryl moieties.
The alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon moieties.
The following examples illustrate the invention.